JP2008525357A - An azole derivative having antimuscarinic activity - Google Patents

Abstract

［式中、Ｒ１、Ｒ２、ｘ、Ｘ、ＹおよびＢは、説明の中で定義する如くである］
で表される化合物に関する。The present invention provides compounds of formula (I) for treating muscarinic acetylcholine receptor mediated diseases, in particular M3 muscarinic receptor mediated diseases.
[Chemical 1]

[Wherein R1, R2, x, X, Y and B are as defined in the description]
It is related with the compound represented by these.

Description

  The present invention relates to antimuscarinic compounds, in particular azole derivatives.

Acetylcholine, a neurotransmitter released from cholinergic neurons in the peripheral and central nervous system, is several by interacting with two major types of acetylcholine receptors: nicotinic and muscarinic acetylcholine receptors Affects the biological processes. Muscarinic receptors are members of the G protein-coupled receptor (GPCR) superfamily and consist of five receptor subtypes (M ₁ , M ₂ , M ₃ , M ₄ , M ₅ ) activated by acetylcholine. Has been. Such receptors are widely distributed in multiple organs and tissues, are important for the maintenance of central and peripheral cholinergic neurotransmission, and can mediate both excitatory and inhibitory effects. Studies and demonstrations of the distribution of such receptor subtypes have been made, for example M ₁ subtype is mainly expressed in neural tissues (cerebral cortex, autonomic ganglia) and M ₂ subtype is mainly in heart Is present in (mediates cholinergic induced bradycardia), while the M3 subtype is primarily present in smooth muscle (airways, bladder, gastrointestinal tract) and salivary glands (1). 2). Each receptor subtype exhibits unique pharmacological properties (Non-Patent Document 3).

  The treatment and pharmaceutical aspects of muscarinic agonists and antagonists have been described (Non-Patent Document 4).

  Muscarinic acetylcholine receptor deficiency has been noted for a variety of pathophysiological conditions.

For example, it has been demonstrated that increased M ₃ receptor subtype stimulation mediates incontinence due to bladder overcontraction;
Gastrointestinal tract in irritable bowel syndrome (IBS) is effected is M _3-mediated hypermotility resulting when inflamed.

In asthma and chronic obstructive pulmonary disease (COPD), by inflammatory conditions, loss of inhibitory M ₂ muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle brought about, vagus nerve it causes Stimulation increases the amount of acetylcholine released. M ₃ stimulation increased leading to airway hyperresponsiveness to mediate as a result of such failure. It can be seen that the degree of vagus nerve-mediated reflex bronchoconstriction increases after viral infection, exposure to ozone or inhalation of antigen. In all cases, failure of inhibitory M ₂ muscarinic receptor for the vagus nerve endings can become a cause of increasing acetylcholine release amount. Anticholinergic compounds may be particularly useful for use, for example, in acute asthma, as reflex bronchoconstriction, triggered by asthma attacks, increases. If it is possible to improve the anticholinergic pharmaceutical (including selective M ₃ antagonist) will result in the effective blockade of such reflex.

  Muscarinic agonists (pilocarpine) and antagonists (atropine) have been known for over a century, but there has been little progress on finding compounds selective for receptor subtypes and antimuscarin used clinically The number of sex compounds is relatively small because of the large side effects. For example, muscarinic antagonists such as atropine are potent bronchodilators, but their clinical use is due to high prevalence of peripheral and central side effects such as tachycardia, blurred vision, dry mouth, constipation, etc. limited. As a result, the development of quaternary derivatives of atropine, such as ipratropium (Non-Patent Document 5), or other quaternary derivatives of scopine, such as Tiotropium (Non-Patent Documents 6 and 7), has allowed acceptance. Has resulted in a method for identifying higher-drug drugs. Nevertheless, they are largely not ideal anticholinergic bronchodilators because of lack of selectivity for muscarinic receptor subtypes.

  Patent Document 1 discloses a 3-substituted oxazolidinedione having anti-inflammatory and bronchodilator activity.

  An azole derivative having muscarinic activity is disclosed in Patent Document 2.

  An azole derivative is disclosed in Patent Document 3 as a selective neurokinin antagonist.

  A 4-imidazolin-2-one derivative is disclosed in Patent Document 4 as a MAP kinase inhibitor useful as a drug, particularly as an anti-inflammatory drug.

  Oxazolidin-2-one is disclosed in Patent Document 5 as a chemokine receptor CCR8 inhibitor useful for the treatment of respiratory diseases such as asthma.

  A dialepanone derivative is disclosed in Patent Document 6 as a CGRP receptor antagonist useful for use in headache, migraine and cluster headache.

  Accordingly, there is a need for highly selective muscarinic antagonists that nevertheless have the ability to interact with individual subtypes to avoid the occurrence of side effects.

U.S. Pat. No. 2,953,481 WO 99/32481 WO 01/44200 WO 03/035638 WO 04/032856 WO 05/072308 Nature, 1986, 323-411 Science, 1987, 237-527 The Muscarinic Receptors, The Humana Press, Inc., 1989, Clifton, NJ Molecules 2001, 6-142 Molecules, 2001, 142-193 Molecules, 2001, 142-193 Eur. Resp. J. 1993, 1031-1036

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of muscarinic acetylcholine receptor mediated diseases, in particular M3 receptor mediated diseases.

  The present invention relates to general formula (I)

{Where,
R ₁ is linear or branched C ₁ -C ₇ alkyl; C ₃ -C ₇ cycloalkyl; phenyl, benzyl, phenyloxymethyl, or optionally the following groups: F, Cl, Br, linear or branched Branch C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methylenedioxy, ethylenedioxy, vinyl, CF ₃ , NO ₂ , CN, COOH, OCF ₃ , CH ₂ OR ₄ , OR ₄ , NR ₄ R ₅ , SO ₂ NR ₄ R ₅ , CONR ₄ R ₅ , SR ₄ , SO ₂ R ₄ , COR ₄ [where R ₄ is H, linear or branched C ₁ -C ₆ alkyl, phenyl, benzyl, or optionally, F, Cl, Br, linear or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methylenedioxy, ethylenedioxy, _{vinyl, CF 3, NO 2, CN} , CH 2 Mono- or fused-heterocycle optionally substituted with OH, and R ₅ is H, linear or branched C ₁ -C ₇ alkyl, CO- (linear or branched C ₁ -C ₇ alkyl) in it either, or R ₄ and R ₅ atomic number of 8 or less Or represents an single or fused heterocycle optionally substituted with one or more of the fused heterocyclic may a have formed,
x is

Is 0 when is a double bond, and

Is 1 when is a single bond,
R ₂ is H or has the same meaning as R ₁ ,
Y represents C═O; CHOH; (CH ₂ ) m, where m is an integer from 1 to 3, or a CH group;
X is sulfur or an NR ₇ group [where R ₇ is hydrogen or a GR ₆ group, where G is selected from CO, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, wherein N is 0-3 and R6 is a H, COOH group or has the same meaning as R ₁ )
B is the following group:
a1)

[Wherein A and A ′, independently of one another, represent a hydrogen, linear or branched C ₁ -C ₄ alkyl group, where m is 0-2 and R ₃ is MR ₆ A group (wherein M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 1-3, and R6 is an H, COOH group; Or has the same meaning as R ₁ )]
a2)

[Wherein A and A ′, independently of one another, represent a hydrogen, linear or branched C ₁ -C ₄ alkyl group, where m is 0-2 and R ₃ is MR ₆ A group (wherein M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 0-3 and R ₆ is an H, COOH group; Or has the same meaning as R ₁ )
b)

[Where R ₆ , m and n are as defined above]
c)

[here,
R ₆ , m and n are as defined above and R ₈ has the meaning R ₁ or the nitrogen atom to which (CH ₂ ) nR ₆ and R ₈ are bound to these Together with optionally forming a phenyl ring, or optionally forming a 4- to 7-membered heterocyclic ring which may be fused with a benzene ring or a single or fused heterocyclic ring. And
Z ⁻ is a pharmaceutically acceptable anion, preferably chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate , Tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, more preferably chloride, bromide, formate, trifluoroacetate or methanesulfonate Is a pharmaceutically acceptable anion selected]
Selected from one of
It is related with the compound represented by these.

  The term “mono- or fused heterocycle” means a heterocyclic ring containing 5 to 10 ring atoms in each ring and no more than 4 heteroatoms selected from S, N, O And pyrrole, pyrazole, furan, thiophene, indole, benzofuran, benzothiophene, imidazole, oxazole, isoxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline and Select from all corresponding saturated and partially saturated heterocycles.

  More preferably, such heterocyclic ring is selected from thiophene, benzothiophene, furan, pyridine.

  A first preferred group of compounds of formula (I) is of formula (IA)

{Where,
B is the formula (IIa)

[Where A and A ′ are preferably hydrogen atoms, where m is 0-2, and R ₃ is preferably an MR ₆ group, where M is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, substituted or unsubstituted phenyl or a single or fused heterocycle]
A group represented by formula (IIb)

[Wherein R ₃ is preferably an MR ₆ group, where M is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, methyl, substituted or non- Substituted phenyl or single or fused heterocycle)]
A group represented by formula (IId)

[Wherein R ₃ is preferably an MR ₆ group, where M is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, methyl, substituted or non- Substituted phenyl or single or fused heterocycle)]
Or a group represented by the formula (IIn)

Or a group represented by formula (IIq)

Is a group represented by
Is a group of compounds represented by

For groups of formula (IIn) and (IIq), A and A ′ are preferably hydrogen, m is 0-1, n is 1, and R ₆ is hydrogen, methyl, substituted or Unsubstituted phenyl or mono- or fused heterocycle and R ₈ is methyl, 2-thienyl-propyl, cyclohexylmethyl, 2-N, N-dimethylaminoethyl, 2-tetrahydrofurylmethyl, carboxymethyl, 2- (5 -Aminopyridinylmethyl), 2- (SO ₃ H) -ethyl, or (CH ₂ ) _n R ₆ and R ₈ together with the nitrogen atom to which they are attached Based on:

Forming one of these.

Moreover, regarding the compound of formula (IA)
R ₁ is preferably optionally selected from phenyl, cyclopentyl; cyclohexyl; benzyl; 2-thienyl and hydrogen optionally substituted as defined above;
R ₂ is preferably hydrogen, optionally phenyl, optionally substituted as defined above, optionally phenoxymethyl, cyclohexyl optionally substituted as defined above; 2-thienyl and methyl Select from the group consisting of and
R ₇ is preferably hydrogen or a GR ₆ group [where G is (CH ₂ ) _n , where n is 1 and R ₆ is methyl, substituted or unsubstituted phenyl or mono- or fused-hetero It is a ring].

  A preferred second group of compounds of the formula (I) are those of the formula (IB)

{Where,
R ₇ is hydrogen,
B is the formula (IIa)

[Where A and A ′ are preferably hydrogen atoms, where m is 0-1 and R ₃ is preferably an MR ₆ group (where M is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, substituted phenyl, or a single or fused heterocycle]
Or a group represented by formula (IIn)

Or a group represented by formula (IIq)

Is a group represented by
Is a group of compounds represented by

A and A ′ in the group represented by formulas (IIn) and (IIq) are preferably hydrogen, m is 0-1, n is 1, and R ₆ is hydrogen, methyl, Substituted or unsubstituted phenyl or mono- or fused heterocycle and R ₈ is methyl, 2-thienyl-propyl, cyclohexylmethyl, 2-N, N-dimethylaminoethyl, 2-tetrahydrofurylmethyl, carboxymethyl, 2 -(5-aminopyridinylmethyl), 2- (SO ₃ H) -ethyl, or (CH ₂ ) _n R ₆ and R ₈ together with the nitrogen atom to which they are attached Become the following group:

Forming one of these.

  A third preferred group of compounds of formula (I) are those of formula (IC)

{Where,
B is the formula (IIa)

Or a group represented by formula (IIf)

[Where A and A ′ are preferably hydrogen, where m is 0-1 and R ₃ is a MR ₆ group, where M is (CH ₂ ) _n Where n is 1-3 and R ₆ is hydrogen, substituted or unsubstituted phenyl, phenoxy, cyclohexyl or a single or fused heterocycle]
Or a group represented by formula (IIb)

[Wherein R ₃ is preferably an MR ₆ group, where M is (CH ₂ ) _n , where n is 0 or 1, and R ₆ is hydrogen, substituted or non- Substituted phenyl or single or fused heterocycle)]
Or a group represented by formula (IId)

[Wherein R ₃ is preferably an MR ₆ group, where M is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, methyl or substituted phenyl or It is a fused heterocycle]
Or a group represented by formula (IIn)

Or a group represented by formula (IIq)

Or a group represented by formula (IIp)

Is a group represented by
Is a group of compounds represented by

A and A ′ in the group represented by the formulas (IIn), (IIq) and (IIp) are preferably hydrogen, m is 0-2, n is 1-3, R ₆ Is hydrogen, phenyl, mono- or fused heterocycle, or optionally SR ₄ , SO ₂ R ₄ , CN, OR ₄ , COR ₄ , CONHR ₄ (where R ₄ is optionally substituted) phenyl, benzyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl, C ₁ -C ₄ optionally C ₁ -C ₄ alkyl optionally substituted with an alkyl selected from), and R ₈ is methyl, 2-thienyl-propyl, cyclohexylmethyl, optionally substituted benzyl, phenoxyethyl, 2-N, N-dimethylaminoethyl; 2-tetrahydrofurylmethyl, carboxymethyl, 2- Selected from (5-aminopyridinylmethyl), 2- (SO ₃ H) -ethyl, or (CH ₂ ) _n R ₆ and R ₈ together with the nitrogen atom to which they are attached. The Serial groups:

Forming one of these.

For the compound of formula (IC)
R ₁ is preferably selected from phenyl, cyclopentyl, cyclohexyl, benzyl, 2-thienyl, optionally optionally substituted as defined above;
R ₂ is preferably selected from the group consisting of hydrogen, optionally phenyl or phenoxymethyl, cyclopentyl; cyclohexyl; 2-thienyl and methyl, optionally substituted as defined above, and
R ₇ is preferably hydrogen or a GR ₆ group [where G is (CH ₂ ) _n , where n is 1 and R ₆ is hydrogen, methyl, substituted or unsubstituted phenyl Or a single or fused heterocyclic ring].

  A fourth preferred group of compounds of formula (I) are those of formula (IE)

{Where:
R ₁ is phenyl;
R ₇ is a GR ₆ group [where G is (CH ₂ ) _n , where n is 1 and R ₆ is phenyl], and
B is preferably of formula (IIa)

Or a group represented by formula (IIb)

Wherein R ₃ is as defined above, and preferably is an MR ₆ group, wherein M is (CH ₂ ) _n , where n is 0-1 and R ₆ is hydrogen, substituted or unsubstituted phenyl or a mono- or fused heterocycle]}
Is a group of compounds represented by

  The compounds of the present invention can be prepared according to the synthetic routes described in Schemes 1-9 below. In Schemes 3-7 and 9, the synthesis route was exemplified using piperidine derivatives [m corresponds to formula (IIa) of 1]. (IIa) (wherein m is 0-2), the same synthetic route can also be used when preparing compounds of the invention having IIb, IIc, IId, IIe.

  Preparation of intermediate hydantoin derivatives (1) and (2) when X = NR7 and Y = CO can be found in the literature (Page, P. et al., Tetrahedron 1992, 48, 7265-7274; Stalker, RA et al., Tetrahedron 2002, 58 4863-4839), and a typical synthetic route used in the synthesis is reported in Scheme 1. For the preparation of hydantoin derivatives of X = NH (1), starting with the corresponding ketone (3a), the Bucherer-Bergs reaction with potassium cyanide and ammonium carbonate is allowed to take place in a sealed stainless steel tube at high temperature. In the alternative, the preparation was carried out using the corresponding diketo derivative (3b) together with urea and potassium hydroxide in ethanol.

  In the second procedure, preparation of the same derivative (1), cyclization of the corresponding amino acid primary amide (4) with urea was performed using the Bucherer-Bergs reaction (Davies, MA et al., J. Med. Chem. 1964, 7, 439-445) was carried out under the same conditions as described above. The preparation of the amino acids can be carried out as described in the literature, for example starting with a keto acid derivative (5) and reacting it with a Grignard reagent to introduce an R2 substituent, thus obtained. The hydroxyl ester can be converted to an aminoamide (4) by heating in a sealed tube with ammonia (Turner, WB et al., J. Chem. Soc Perkin Trans. 1967, 2225-2228).

  In the preparation of the substituted hydantoin derivative (2) where R7 ≠ H, the amino-amide derivative (4) is reacted with the appropriate reactant R7-Z where Z is an appropriate leaving group as in the case of the derivative (6). Similarly, the amino group is functionalized (for a general review of amino group reactivity, see Smith, MB, March, J. Advanced Organic Chemistry, Wiley, 2001). Next, as described with respect to compound (1), cyclization to give hydantoin occurred in a sealed ring with urea, or alternatively, the corresponding p-nitrophenyl carbamate was generated. Hydantoin is obtained in two steps by subsequent cyclization with sodium hydroxide (De Lucca, GV et al., J. Med. Chem. 2002, 45, 3794-3804).

  For the preparation of heterocyclic intermediates of Y = O and X = O, S, such as (7) or (8), the synthetic route shown in Scheme 2 was followed.

  Corresponding to reacting a keto-ester or thio-ketoester derivative (9) with a Grignard compound as described in the literature (Mayrargue, J. et al., Bull. Soc. Chim. Fr. 1984, 129-132) Α-hydroxy or α-mercaptoester was obtained. The ester was treated with ammonia in 60 ° C. methanol to convert it to the primary amide (10). Cyclization occurs by heating in a sealed tube with urea, or alternatively, p-nitrophenyl carbonate (or thiocarbonate) is formed followed by cyclization using sodium hydroxide. The cyclization takes place in a two-step procedure involving

  Intermediate (11) can be obtained by subjecting X = S, NR7 intermediate (1), (2), (8) to further functionalization at the nitrogen atom located at position 3 as described in Scheme 3. Was generated. Amino-alcohols where the amino group is suitably protected as a protecting group (PG), such as t-butyloxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) derivatives, or alternatively as benzyl or methyl derivatives Reactant (12) and intermediates (1), (2), (8) composed of the following are described in the literature (Pelletier, JC et al., Tetr Lett. 2001, 41, 797-800) with respect to hydantoin or similar compounds (11) was obtained by reacting with Mitsunobu reaction as described.

  Using various synthetic routes, the mesolate derivative (13) or alcohol group is the leaving group after deprotonating the nitrogen at the 3-position of the intermediate (1), (2), (8). Their functionalization can be achieved by reacting with similar derivatives activated as: Reaction of compound (12) with mesyl chloride and triethylamine in methylene chloride as described in the literature (Bentley, J. et al., J. Chem. Soc. Perkin Trans. 1994, 2, 2531) Intermediate (13) can be obtained.

  Subsequent modification of intermediate (11) was accomplished as described in Scheme 4 to yield derivatives where Y = CHOH or Y = CH and R2 formed a bond with Y.

Reduction with sodium bis- (2-methoxyethoxy) aluminum hydride (Red-Al) or a mixture of LiAlH ₄ and AlCl ₃ at room temperature (Knabe, J. et al., Arch. Pharm. (Weinheim), 1993, 326, 331-334) to obtain the hydroxy derivative (14), then when R2 = H, it can be converted to the unsaturated compound (15) under mildly acidic conditions. Derivative (11) was reduced with Red-Al or LiAlH ₄ + AlCl ₃ in refluxing THF to give saturated intermediate (16) (Marquez, VE et al., J. Org. Chem. 1972, 37 (16), 2558-2561).

Further functionalization was achieved as shown in Scheme 5 by introducing the substituent R3 to give the final compounds (17), (18), (19), (20), (21). The removal of the protecting group PG, suitably BOC or CBz or benzyl or methyl, is described in the literature, i.e. for example the removal of the BOC group using HCl in Et ₂ O (Stahl, GL et al., J. Org Chem .. 1978, 43, 2285), removing CBz or benzyl groups by hydrogenation with palladium on charcoal (Bergman, M. et al., Chem. Ber. 1932, 65, 1192) In the case of methyl group, treatment with α-chloroethyl chloroformate followed by hydrolysis with sodium hydroxide (Olofsen, RA et al., J. Org. Chem. 1984, 49, 2081-2082) It carried out in.

  The compound described as (17) can be considered as the final compound or as an intermediate for introducing the residue R3.

  The introduction of residue R3 can be carried out using any means described in the literature for the functionalization of secondary amino groups, i.e. alkylation, reductive amination, arylation, acylation, sulfonylation, isocyanide and (See Smith, MB, March, J. Advanced Organic Chemistry, Wiley, 2001 for a general review on the reactivity of amino groups).

  An organic or inorganic acid (for example, hydrochloric acid, hydrobromic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, etc.) is added to the compound (18) in which R3 is such that the nitrogen atom maintains the properties of a tertiary amino group. Further functionalization by treatment with can yield an ammonium salt of type (19) and also convert compound (18) to a quaternary ammonium salt, such as compound (20). (Lim, L. et al., Tetr. Lett. 1997, 38, 3243) or N-oxide derivatives (21) (Albin, A. et al., Heterocyclic N-Oxides, CRC Press, 1991, 31) It is also possible.

  As an alternative synthesis route, the substituent R3 can be introduced at an earlier stage of synthesis as shown in Scheme 6.

  Functionalization using any means described in the literature for functionalizing a secondary amino group in compound (22), ie alkylation, reductive amination, arylation, acylation, sulfonylation, isocyanate (See Smith, MB, March, J. Advanced Organic Chemistry, Wiley, 2001 for a general review on the reactivity of amino groups) to give intermediate (23). According to the same procedure described in Scheme 3 above, compound (23) is reacted with intermediate (1), (2) or (8) by Mitsunobu reaction or alkylation to give compound (24). Obtainable. Such a compound can be a final compound or it can be reduced to some extent or completely in a procedure similar to the procedure described in Scheme 4 above, to give the final compound (26) or (27) can be obtained.

  Moreover, any final compound (24), (26), (27) can be further functionalized as an ammonium salt, as a quaternary ammonium salt or as an N-oxide derivative in Scheme 5 above. It can also be received as described.

  In the case of the final compound of X = N-R7, the substituent R7 can be introduced at a later stage of the synthesis by adopting an alternative synthetic route as described in Scheme 7.

  Appropriate reactant R7-Z (where Z is the same) for compound (28) (when X = NH) which can be considered as the final compound and can be prepared as described in Scheme 6 above. Alkylation or arylation or acylation or sulfonylation reactions with the appropriate leaving group) may be performed. The final compound (29) thus obtained can be further reacted as described in Scheme 4 above to give the final compounds (30) and (31).

  Moreover, any final compound (29), (30), (31) can be further functionalized as an ammonium salt, as a quaternary ammonium salt or as an N-oxide derivative in Scheme 5 above. It can also be received as described.

For the synthesis of intermediates (37) and (38), when Y = CH ₂ , a different synthetic route as described in Scheme 8 below can be employed as an alternative to the method described in Schemes 1 and 2.

  The amino acid primary amide (4) was prepared as described in Scheme 1.

  The primary amide group was reduced using the reaction conditions described in the literature (Challis, BC et al., The Chemistry of Amides, 1970, Wiley, 795; Brown, HC et al., Tetr. 1992, 41, 996). Thus, a primary amino group can be generated. For example, an intermediate (33) can be obtained by reacting with a borane-dimethyl sulfide complex or lithium aluminum hydride. Alternatively, compound (4) can be reacted with the appropriate reactant R7-Z (where Z is a suitable leaving group) to functionalize the primary amino group it contains. Intermediate (34) can be obtained, which can then be reduced to give the primary amine (35).

  Next, imidazolidines (37) and (38) can be obtained by subjecting intermediates (33) and (35) to a cyclization reaction, respectively. This cyclization step can be achieved using procedures described in the literature, such as carbonyldiimidazole (De Cicco, P. et al., Bioorg. Med. Chem. Lett. 1997, 7 (18), 2331-2336. ) Or phosgene or triphosgene (Gawley, RE et al., J. Org. Chem. 1996, 61, 8103-8112) as the carbonyl group source; alternatively, the corresponding p-nitrophenyl carbamate or It is also possible to achieve the same cyclization in two steps by cyclization with sodium hydroxide after formation of carbonate (Akiba, T. et al., Tetrahedron 1994, 50 (13), 3905- 3914).

  In the same manner as described in Scheme 8, in the case of the final compound (27) described in Scheme 6, an alternative synthetic route can be employed. An outline of the synthetic route is shown in Scheme 9.

  Preparation of the amide (40) of the amino acid is carried out as described in the literature (Challis, BC et al., The Chemistry of Amides, 1970, Wiley, 795), e.g. with condensing agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole. Implemented.

  Reduction to the amide group is carried out in the reaction conditions described in the literature (Challis, BC et al., The Chemistry of Amides, 1970, Wiley, 795; Brown, HC et al., Tetr. 1992, 41, 996), e.g. borane-dimethyl sulfide. The intermediate (42) can be obtained by using a complex or lithium aluminum hydride or the like to make it a primary amino group. By subjecting this intermediate to cyclization using, for example, carbonyldiimidazole or triphosgene, the final compound (44) can be obtained.

  The compounds of the above formula (I) have antimuscarinic activity, in particular they show a potent interaction with the M3 subtype. They also show different selectivity for muscarinic receptors M1 and M2 and urinary incontinence such as respiratory, urinary or gastrointestinal diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough, emphysema and rhinitis It can be used for the purpose of producing a pharmaceutical composition for the treatment of bladder related diseases, irritable bowel syndrome.

  A compound or composition of the invention can be prepared for administration by any route, preferably it is administered in a unit dosage form or by a human patient in a single dosage form to themselves. Make it possible. The composition is preferably suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. It is also possible to devise a formulation so that the active ingredient is released slowly.

  Standard pharmaceutical compositions can be prepared using conventional methods and excipients.

  The invention is illustrated in more detail in the following experimental section of this specification.

Experimental Section The affinity of the compounds of the present invention for muscarinic receptor subtypes M ₁ , M ₂ , M ₃ was determined by a radioligand binding assay (performed as described below).

CHO-K1 clonal cell (respectively Swissprot P11229, P08172, P20309) expressing the prepared human M _1, M ₂ or M ₃ receptor cell lines and membrane of these Ca ⁺⁺ / Mg ⁺⁺ free phosphate buffered saline After being harvested, it was collected by centrifugation at 1500 rpm for 3 minutes. The precipitate was resuspended in ice-cold buffer A (15 mM Tris-HCl pH 7.4, 2 mM MgCl ₂ , 0.3 mM EDTA, 1 mM EGTA) and then PBI polytron (15 to 5). (Set to seconds). The crude membrane fraction was collected by carrying out the step of centrifuging at 40000 g for 20 minutes at 4 ° C. twice (separated in the washing step using buffer A). The resulting precipitate was finally resuspended in buffer B (75 mM Tris HCl pH 7.4, 12.5 mM MgCl ₂ , 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose) and aliquoted. Separately and stored at -80 ° C.

Radioligand binding conditions Frozen membranes were resuspended in buffer C (50 mM Tris-HCl pH 7.4, 2.5 mM MgCl ₂ , 1 mM EDTA) on the day of the experiment. The non-selective muscarinic radioligand [ ³ H] -N-methylscopolamine (Mol. Pharmacol. 45: 899-907) was used to label the M1, M2 and M3 binding sites. Binding experiments were performed using 96-well plates with overlapping radioligand concentrations of 0.1-0.3 nM (10-point concentration curve). Nonspecific binding was measured in the presence of 10 mM cold N-methylscopolamine. Samples (final volume 0.75 ml) were incubated at room temperature for 120 minutes for M ₁ binding assays, 60 minutes for M ₂ binding assays and 90 minutes for M ₃ binding assays. The reaction was stopped by rapid filtration through GF / B Unifilter plates followed by two washes (0.75 ml) with cold buffer C using a Packard Filtermate Harvester. The radioactivity exhibited by the filter was measured with a microplate scintillation counter TopCount NXT (Camberra Packard).

Preparation Example Procedure 1-Intermediate (1) described in Scheme 1
Synthesis of 5-phenyl-5-cyclohexyl hydantoin (1a) Cyclohexylphenyl ketone (0.564 g, 3 mmol) is dissolved in a 1: 1 mixture of ethanol and water (20 mL) in a stainless steel sealed tube. Potassium cyanide (0.585 g, 9 mmol) and ammonium carbonate (3.28 g, 30 mmol) are added and the mixture is heated to 100 ° C. for 18 hours.

  The reaction mixture is then cooled to room temperature, diluted with 20 mL of water, and then cooled to 0 ° C. to precipitate the desired product as a white solid that is filtered to produce a high purity product. 0.70 g is obtained.

  The synthesis of hydantoin derivatives (1b)-(1g) was carried out according to the same procedure starting from the corresponding commercial ketone. In the case of compounds (1b) and (1c), the starting ketone derivative was prepared as described in Reichard, G.A. et al., Org. Lett. 2003 5 (23), 4249-4251.

  The synthesis of the hydantoin derivative (1i) was carried out according to the same procedure 1, starting from the corresponding commercial ketone.

Step 2-Intermediate described in Scheme 1 (1)
Synthesis of 5,5-di- (4-fluorophenyl) hydantoin (1h) Bis- (4-fluorophenyl) -ethanedione (1.23 g, 5 mmol) was dissolved in ethanol (20 mL) and urea (0.39 g, 6.5 mmol) and potassium hydroxide (pellet, 0.476 g, 8.5 mmol) are added and the resulting mixture is heated to 80 ° C. for 24 hours. The reaction is cooled to room temperature, diluted with water (40 mL) and then cooled to 0 ° C., whereupon the desired product precipitates as a white solid that is filtered to yield a highly pure product. Get 0.62 g.

  The synthesis of the hydantoin derivative (1j) was carried out according to the same procedure 2, starting from the corresponding commercial ketone.

Step 3-Intermediate (2) described in Scheme 1
Synthesis of 1-benzyl-5-phenylhydantoin (2a)
1. N-benzylphenylglycinamide
N-benzylphenylglycine ethyl ester (prepared as described in Browne, L. et al., J. Org. Chem. 1952, 17, 1187-1190) in an amount of 0.57 g (2.1 mmol) ethanol (20 Add to 30% aqueous ammonia (8 mL). After the mixture was heated to 60 ° C. for 8 hours, the solvent was evaporated to give the product as an oil (0.51 g), which was used in the next step without further purification.
2. N-Benzyl-N- (4-nitrophenylcarbamoyl) phenylglycinamide
N-benzylphenylglycinamide (0.51 g, 2.08 mmol) is dissolved in anhydrous THF (15 mL) under a nitrogen atmosphere. N-methylmorpholine is added and the reaction mixture is cooled to 0 ° C., followed by 4-nitrophenyl chloroformate (642 mg, 3.18 mmol). The reaction was stirred at room temperature for 2 hours, the solvent was evaporated under vacuum, the residue was dissolved in ethyl acetate, extracted with water followed by brine, and finally dried and then under vacuum. Concentration gives an orange oil (0.82 g) which is used in the next step without further purification.
3. 1-Benzyl-5-phenylhydantoin (2a)
N-benzyl-N- (4-nitrophenylcarbamoyl) phenylglycinamide (0.82 g, 2.02 mmol) is dissolved in methanol (20 mL), and then 3 mL of 2M sodium hydroxide solution is added. The mixture is stirred at room temperature for 2 hours.

The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and extracted with saturated NaHCO ₃ solution, water followed by brine, finally dried and concentrated in vacuo to a yellow color. A solid is obtained, which is crystallized from methanol to give the desired product as a white solid (0.27 g).

Step 4
Intermediates described in Scheme 3 (11)
And the final compound described in Scheme 6 (24)
Synthesis of 3- (1-benzyl-piperidin-4-yl) -5,5-diphenyl-imidazolidine-2,4-dione (24a) Commercially available 5,5-diphenylhydantoin (phenytoin, 0.50 g, 1.98 mmol) Is dissolved in anhydrous THF (20 mL) and triphenylphosphine (0.78 g, 2.97 mmol) and 4-hydroxy-N-benzylpiperidine (0.567 g, 2.97 mmol) are added to the reaction mixture. The resulting solution is cooled to 0 ° C. and then diethyl aza-dicarboxylate (DEAD, 0.47 mL) is added dropwise. The reaction is then stirred at room temperature for 24 hours. After evaporating the solvent under vacuum, the product is purified by column chromatography over silica gel (500 g, eluent: AcOEt: hexane = 2: 8 to AcOEt) to give a high purity product as a white solid, 0.8 Get g.

  The synthesis of the compounds described in Table 4 was carried out following the same procedure starting from the corresponding hydantoin or oxazolidine-2,4-dione.

Step 5
Intermediate (11) described in scheme 3 and final compound (24) described in scheme 6
1. Synthesis of methanesulfonic acid 8-methyl-8-aza-bicyclo [3.2.1] octo-3-yl ester (tropine sylate ) Tropine (0.150 g, 1.063 mmol) and triethylamine (0.207 mL, 1.5 mmol) in anhydrous DCM (10 mL) is added to the resulting solution, and the resulting mixture is cooled to 0 ° C. before adding mesyl chloride (0.099 mL, 1.276 mmol). The reaction was stirred at 0 ° C. for 1 hour and then the solvent was evaporated in vacuo to give the product as a white solid that was used in the next step without purification.
2. Synthesis of 3- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -5,5-diphenyl-imidazolidine-2,4-dione (24l) Commercially available 5,5-diphenyl Hydantoin (phenytoin, 0.20 g, 0.793 mmol) was dissolved in anhydrous DMF (10 mL), and then K ₂ CO ₃ (0.33 g, 2.38 mmol) and tropine mesylate (prepared above) were added to anhydrous DMF ( Dissolve in 3 mL) and add. The reaction is then stirred at 80 ° C. for 18 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, and the organic phase is washed with water followed by brine, finally dried and concentrated in vacuo to give a yellowish solid. It is crystallized from ethyl ether to give the desired product as a white solid (0.18 g).

  The synthesis of the compounds described in Table 5 was carried out according to the same procedure starting from the corresponding hydantoin.

Step 6
Intermediate (16) described in Scheme 4 and the final compound described in Scheme 6 (27)
Synthesis of 3- (1-benzyl-piperidin-4-yl) -5,5-diphenyl-imidazolidin-2-one (27a) (24a) (1.0 g, 2.3 mmol) in anhydrous THF (20 mL) Dissolve under nitrogen atmosphere. After cooling the solution to 0 ° C., a 3.5 M sodium bis- (2-methoxyethoxy) aluminum hydride (Red-Al) solution in toluene (5.37 mL, 18.4 mmol) is added. The mixture is then heated to 85 ° C. for 4 hours. The reaction was again cooled to 0 ° C., quenched with water (5 mL), 2M sodium hydroxide (10 mL) was added, and the mixture was extracted with ethyl acetate, The organic phase is washed with water followed by brine, finally dried and then concentrated under vacuum to give a yellowish solid which is crystallized from acetone to give the desired product. Is obtained as a white solid (0.80 g).

The synthesis of the compounds described in Table 6 was carried out in the same procedure starting from the corresponding hydantoin.
Step 7
Intermediate (16) described in Scheme 4 and the final compound described in Scheme 6 (27)
Synthesis of 1-benzyl-3- (1-benzyl-piperidin-4-yl) -5-phenyl-imidazolidin-2-one (27r) Lithium aluminum hydride (0.309 g, 8.16 mmol) was added to anhydrous THF (15 ml ) In a nitrogen atmosphere and suspended. The suspension is cooled to 0 ° C. and then a solution formed by placing aluminum trichloride (1.085 g, 8.16 mmol) in anhydrous THF (10 mL) is added. The resulting mixture is stirred at 0 ° C for 30 minutes. Next, the resulting solution of compound (24o) (0.5 g, 2.04 mmol) in anhydrous THF (12 mL) was added to the LiAlH ₄ + AlCl ₃ mixture and the resulting suspension was added to 65 mL. Heat to ° C for 3 hours. The reaction was again cooled to 0 ° C and quenched with water (5 mL), then 1M sodium hydroxide (10 mL) was added and the mixture was extracted with ethyl acetate. The organic phase is washed with water followed by brine, finally dried and then concentrated under vacuum to give a yellowish solid which is crystallized from acetone to give the desired product. Is obtained as a white solid (0.310 g).

  The synthesis of the compounds described in Table 7 was carried out in the same procedure starting from the corresponding hydantoin.

Step 8
Intermediate (15) described in scheme 4 and final compound described in scheme 6 (26)
3-benzyl-1- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -4-phenyl-1,3-dihydro-imidazol-2-one (26o) 24o) (1.0 g, 2.3 mmol) is dissolved in anhydrous THF (20 mL) under a nitrogen atmosphere. After cooling the solution to 0 ° C., a 3.5 M sodium bis- (2-methoxyethoxy) aluminum hydride (Red-Al) solution in toluene (5.37 mL, 18.4 mmol) is added. The mixture is then stirred at room temperature for 24 hours. The reaction is again cooled to 0 ° C., quenched with water (5 mL), 1M hydrochloric acid (10 mL) is added, and the mixture is stirred at room temperature for 30 minutes. After adding 2M sodium hydroxide (15 mL) to the reaction mixture, it was extracted with ethyl acetate and the organic phase was washed with water followed by brine and finally dried. Concentrate in vacuo to give a yellowish oil that is purified by reverse phase chromatography (C-18 coated SiO ₂ , 500 g; eluent: MeOH: H ₂ O = 1: 1) To give the desired product as a white solid (0.262 g).

Step 9
Intermediates described in Scheme 5 (17)
Synthesis of 4,4-diphenyl-1-piperidin-4-yl-imidazolidin-2-one (17a) (27a) (0.50 g, 1.2 mmol) dissolved in methanol (15 mL) and water (5 mL) Let After adding 37% hydrochloric acid (0.5 mL) and palladium on charcoal (0.20 g), the solution is hydrogenated in a Parr apparatus (H ₂ : 20 psi) at room temperature for 8 hours. After the catalyst is removed by filtration, the clear solution is evaporated to give the pure product as a white solid (0.380 g).

  The synthesis of the other compounds described in Table 9 was carried out according to the same procedure 9 starting from the corresponding tertiary benzylamine.

Compound (17a) can also be prepared according to different procedures starting from the same intermediate.
Step 10
Intermediates described in Scheme 5 (17)
Synthesis of 4,4-diphenyl-1-piperidin-4-yl-imidazolidin-2-one (17a) (27b) (0.125 g, 0.37 mmol) dissolved in anhydrous toluene (20 mL) -Chloroethyl (0.075 mL, 0.74 mmol) is added and the reaction mixture is refluxed for 3 hours. The solvent is evaporated under vacuum, the residue is dissolved in methanol (20 mL) and 10% aqueous NaOH (5 mL) is added. The mixture is heated to 60 ° C. for 3 hours and then the solvent is evaporated under vacuum. The residue is dissolved in water and extracted with ethyl acetate, and the organic phase is washed with water followed by brine, finally dried and concentrated in vacuo to give a yellowish solid. Te, flash chromatography (SiO _2, 60 g; eluent: DCM: MeOH = 9: 1 ) the desired product in purified by as a white solid (0.085 g).

  The synthesis of the compounds described in Table 9 bis was carried out according to the same procedure 10, starting with the corresponding tertiary methyl or benzylamine.

Step 11
Final product described in Scheme 5 (18)
1- [1- (3,5-Bis-trifluoromethyl-benzyl) -piperidin-4-yl] -4,4-diphenyl-imidazolidin-2-one (18a) synthetic compound (17a) (0.100 g , 0.311 mmol) in anhydrous DCM (10 mL) followed by the addition of solid K ₂ CO ₃ (0.20 g, 1.45 mmol). The mixture is stirred vigorously at room temperature before 3,5-bis-trifluoromethyl-benzyl bromide (0.057 mL, 0.311 mol) is added. After the reaction was stirred at room temperature for 5 hours, solid K ₂ CO ₃ was filtered off and the solution was evaporated to give a colorless oil which was crystallized from di-isopropyl ether. To give a highly pure product as a white solid (0.060 g).

  Synthesis of the compounds described in Table 10 was carried out using (17a) or by starting with the intermediates shown in the table and reacting it with the corresponding alkylating agent according to the same procedure 11.

Step 12
Final product described in Scheme 5 (18)
1- [1- (4-Chloro-benzyl) -piperidin-4-yl] -4,4-diphenylimidazolidin-2-one (18q)
Compound (17a) (0.100 g, 0.311 mmol) is dissolved in methanol (10 mL) under a nitrogen atmosphere, and then 4-chlorobenzaldehyde (0.050 g, 0.341 mmol) is added. The mixture is stirred at room temperature for 30 minutes before solid NaBH ₃ CN (0.040 g, 0.622 mmol) is added. The reaction is stirred at room temperature for 18 hours before the solvent is evaporated under vacuum. The residue is dissolved in water and extracted with ethyl acetate, and the organic phase is washed with water followed by brine, finally dried and concentrated in vacuo to give a yellowish solid. It is purified by flash chromatography (SiO ₂ , 6 g; eluent: DCM: MeOH = 9: 1) to give the desired product as a white solid (0.074 g).

  The compounds described in Table 11 were synthesized by reacting with the corresponding aldehyde starting from (17a) according to the same procedure.

Step 13
Synthesis of the final product (19) described in Scheme 5
1-Benzyl-1-methyl-4- (2-oxo-4,4-diphenylimidazolidin-1-yl) -piperidinium iodide (19)
Compound (27a) (0.040 g, 0.097 mmol) is dissolved in dichloromethane (2 ml). Then methyl iodide (0.2 ml, 3.212 mmol) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated to give a high purity product as a white solid (0.035 g).

  Synthesis of the compounds described in Table 12 and Table 12 bis was carried out according to the same procedure, starting with the corresponding tertiary amino derivative and the appropriate alkylating agent.

Step 13b
Final product described in Scheme 5 (21)
Synthesis of 1- [1-benzyl-1-oxy) -piperidin-4-yl] -4,4-diphenyl-imidazolidin-2-one (21a) (27a) (0.100 g, 0.243 mmol) in anhydrous DCM (3 ml) is dissolved under nitrogen atmosphere. The reaction mixture is cooled to 0 ° C. and m-chloroperbenzoic acid (0.063 g, 0.364 mmol) is added. The reaction is stirred at 0 ° C. for 30 minutes followed by 3 hours at room temperature.

  The reaction mixture is then diluted with DCM and washed twice with saturated potassium carbonate solution, water and brine.

  The organic phase is dried and evaporated to give the pure product as a white solid (0.075 g).

  Compound (21b) described in Table 13 was synthesized according to the same procedure 13b starting from intermediate (18ar).

Step 14
Final product described in Scheme 9 (44)
Synthesis of 1- (1-benzyl-piperidin-4-yl) -3-methyl-4-phenyl-imidazolidin-2-one (44a)
1. 2- (Nt-butyloxycarbonyl) -amino-2-phenyl-N- (1-benzyl-piperidin-4-yl) -acetamide Commercial N-BOC protected phenylglycine (5.0 g, 19.9 mmol) Is suspended in a mixture of acetonitrile (50 mL) and dichloromethane (50 mL). The suspension is stirred vigorously under a nitrogen atmosphere. N-hydroxybenzotriazole (2.97 g, 22 mmol) and dicyclohexylcarbodiimide (4.53 g, 22 mmol) are added and the mixture is stirred at room temperature for 2 hours. 4-Amino-N-benzylpiperidine (4.18 g, 22 mmol) is added and the reaction is stirred overnight at room temperature.

The reaction mixture is then diluted with DCM and washed twice with saturated potassium carbonate solution, water and brine. The organic phase was dried and concentrated in vacuo to give an oil that was purified by flash chromatography (SiO ₂ , 120 g; eluent: DCM: MeOH = 95: 5). The product is obtained as a white solid (6.4 g).
2. 2-Amino-N- (1-benzyl-piperidin-4-yl) -2-phenylacetamide dihydrochloride
2- (N-t-butyloxycarbonyl) -amino-2-phenyl-N- (1-benzyl-piperidin-4-yl) -acetamide was dissolved in dichloromethane (80 mL), and then hydrogen chloride was added to diethyl ether. (50 mL) was added to the saturated solution formed. The reaction mixture is stirred at room temperature for 4 hours. The desired product precipitates as a white solid, which is then filtered and then dried under vacuum (4.5 g).
3. N-2- (1-Benzylpiperidin-4-yl) -1-phenylethane hydrochloride, 2-amino-N- (1-benzylpiperidin-4-yl) -2-phenyl hydrochloride To a solution of acetamide (0.44 g, 1.15 mmol) in anhydrous toluene (10 ml) was added borane-methyl sulfide complex (0.22 ml, 2.3 mmol) under an inert atmosphere. The mixture was refluxed for 4 hours and MeOH (0.5 ml) was added. After 1 hour, the solution was cooled and treated with 10% HCl solution in ethyl ether (10 ml). The white precipitate was filtered and washed with ether (0.45 g).
4. 1- (1-Benzylpiperidin-4-yl) -4-phenylimidazolidin -2- one hydrochloride N-2- (1-benzylpiperidin-4-yl) -1-phenylethane-1,2-diamine Carbonyl-diimidazole (0.2 g, 1.14 mmol) was added to a suspension formed by placing (0.4 g, 0.95 mmol) in anhydrous 1,4-dioxane (10 ml). The mixture was refluxed for 2 hours and the solvent was removed. The crude material was treated with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid (0.22 g).

  The synthesis of the other compounds described in Table 14 was carried out according to the same procedure 14, starting from the corresponding commercially available starting materials.

Step 15
Final product described in Scheme 7 (30)
Synthesis of 1- (1-benzyl-piperidin-4-yl) -3-methyl-4-phenyl-imidazolidin-2-one (30a) (44a) (0.100 g, 0.243 mmol) in anhydrous THF under nitrogen atmosphere Dissolve below and cool the solution to 0 ° C. before adding solid NaH (0.010 g, 0.243 mmol). The reaction is stirred at 0 ° C. for 15 minutes, then benzyl bromide (0.042 g, 0.243 mmol) is added and stirring is continued at room temperature for 3 hours. The reaction is diluted with water and extracted with ethyl acetate, and the organic phase is washed with water followed by brine, finally dried, and concentrated in vacuo to give an oil that Is purified by preparative HPLC to give the desired product as a white solid (0.041 g).

  The synthesis of the compounds described in Table 15 was carried out following the same procedure starting from the corresponding derivatives and the appropriate alkylating agent.

Step 16
Final product described in Scheme 9 (30)
1- (1-Benzyl-piperidin-4-yl) -3,4-diphenyl-imidazolidin-2-one (30aa)
Compound (44a) (100 mg, 0.3 mmol) is dissolved in DMF (1 mL). After adding iodobenzene (0.067 mL), copper (I) iodide (60 mg) and K ₂ CO ₃ (40 mg), the resulting mixture is heated to 150 ° C. under nitrogen atmosphere for 4 hours. The mixture is then diluted with ethyl acetate, filtered over a pad of celite and the resulting solution is dried under vacuum. The product is purified by preparative HPLC to yield 45 mg of highly pure product as a white solid.

  The same procedure 18 was followed starting from the intermediate describing the synthesis of the compounds described in Table 16.

Step 17
Final product described in Scheme 5 (18)
Dissolve tributyltin azide sodium azide (265 mg, 4 mmol) in water (4 mL). The solution is cooled to 0 ° C. and tributyltin chloride (1.08 mL, 4 mmol) is added dropwise. After the solution was stirred at room temperature for 2 hours, the aqueous mixture was extracted twice with methylene chloride, the organic phase was dried over MgSO ₄ and the solvent was evaporated under vacuum to azide. 980 mg of tributyltin is obtained.
4,4-diphenyl-1- [1- (1H-tetrazol-5-ylmethyl) -piperidin-4-yl] -imidazolidin-2-one compound (18 m) (100 mg, 0.27 mmol) without mixture Of tributyltin azide (980 mg) at 100 ° C for 4 hours. The reaction mixture is then cooled to room temperature, methanol (3 mL) and 2N HCl (1 mL) are added, and the resulting mixture is stirred at room temperature for 1 hour. The solution was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil that was chromatographed on silica gel. Purification with (eluent: dichloromethane: methanol 95: 5) gives the desired product as a yellow solid (61 mg).

  The compounds described in Table 17 were synthesized according to the same procedure starting from the corresponding cyano derivative.

Step 18
(3-Hydroxymethyl-phenyl) -carbamic acid ethyl ester
3-Amino-benzyl alcohol (1.0 g, 8.1 mmol) (1.36 mL, 9.7 mmol) is dissolved in anhydrous dichloromethane (15 mL). The resulting solution is cooled to 0 ° C. and then ethyl chloroformate (0.86 mL, 8.9 mmol) is added dropwise. The mixture was stirred at 0 ° C. for 2 hours, then aqueous K ₂ CO ₃ (1M, 20 mL) was added, the mixture was extracted twice with dichloromethane, the organic phase was washed with brine, After drying over anhydrous sodium sulfate, concentration under reduced pressure gives the desired product as an orange oil that is purified by chromatography on silica gel (eluent: dichloromethane: methanol 95: 5). To give the desired product as a light yellow oil (1.0 g).
Methanesulfonic acid 3-ethoxycarbonylamino-benzyl ester
(3-Hydroxymethyl-phenyl) -carbamic acid ethyl ester (0.63 g, 3.2 mmol) and triethylamine (0.59 mL, 4.2 mmol) are dissolved in anhydrous dichloromethane (10 mL). The resulting solution is cooled to 0 ° C. and methanesulfonyl chloride (0.28 mL, 3.58 mmol) is added dropwise. The resulting mixture was stirred at room temperature for 2 hours, then an aqueous K2CO3 solution (1M, 20 mL) was added, the mixture was extracted twice with dichloromethane, and the organic phase was washed with brine, After drying over anhydrous sodium sulfate, it is concentrated under reduced pressure. The desired product is further purified by chromatography on silica gel (eluent: ethyl acetate: hexane 9: 1) to give a colorless oil (0.13 g).
Compound (18aq):
Synthesis of 1- [1- (3-methylamino-benzyl) -piperidin-4-yl] -4,4-diphenyl-imidazolidin-2-one compound (18aq) was started using intermediate (17a). The following two steps were carried out:
Step 1: Alkylation of (17a) with methanesulfonic acid 3-ethoxycarbonylamino-benzyl ester is carried out as described in procedure 12 to give {3- [4- (2-oxo-4,4-diphenyl -Imidazolidin-1-yl) -piperidin-1-ylmethyl] -phenyl} -carbamic acid ethyl ester was obtained.
Step 2: The reduction to {3- [4- (2-oxo-4,4-diphenyl-imidazolidin-1-yl) -piperidin-1-ylmethyl] -phenyl} -carbamic acid ethyl ester was described in Procedure 6. To give the desired compound.

The compounds of the present invention exhibit anti-muscarinic M ₃ activity in radioligand binding assays according to the methods described above. Binding affinity shown compounds against M ₃ receptors of the present invention is in the range of 0.1 to 2000 nM (Ki), the Ki of the most preferred compounds exhibited a range of 0.1 to 100 nM. The following data shows some examples:

Claims (14)

Formula (I)

{Where,
R ₁ is linear or branched C ₁ -C ₇ alkyl; C ₃ -C ₇ cycloalkyl; phenyl, benzyl, phenyloxymethyl, or optionally the following groups: F, Cl, Br, linear or branched Branch C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methylenedioxy, ethylenedioxy, vinyl, CF ₃ , NO ₂ , CN, COOH, OCF ₃ , CH ₂ OR ₄ , OR ₄ , NR ₄ R ₅ , SO ₂ NR ₄ R ₅ , CONR ₄ R ₅ , SR ₄ , SO ₂ R ₄ , COR ₄ [where R ₄ is H, linear or branched C ₁ -C ₆ alkyl, phenyl, benzyl, or optionally, F, Cl, Br, linear or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methylenedioxy, ethylenedioxy, _{vinyl, CF 3, NO 2, CN} , CH 2 Mono- or fused-heterocycle optionally substituted with OH, and R ₅ is H, linear or branched C ₁ -C ₇ alkyl, CO- (linear or branched C ₁ -C ₇ alkyl) in it either, or R ₄ and R ₅ atomic number of 8 or less Or represents an single or fused heterocycle optionally substituted with one or more of the fused heterocyclic may a have formed,
x is

Is 0 when is a double bond, and

Is 1 when is a single bond,
R ₂ is H or has the same meaning as R ₁ ,
Y represents C═O; CHOH; (CH ₂ ) m, where m is an integer from 1 to 3, or a CH group;
X is sulfur or an NR ₇ group [where R ₇ is hydrogen or a GR ₆ group, where G is selected from CO, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, wherein N is 0-3 and R6 is a H, COOH group or has the same meaning as R ₁ )
B is the following group:
a1)

[Wherein A and A ′ independently of one another represent a hydrogen, linear or branched C ₁ -C ₄ alkyl group,
m is 0-2, and
R ₃ is selected from MR ₆ groups (where M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 1-3 and R6 is , H, COOH group, or the same meaning as R ₁ )]
a2)

[Wherein A and A ′ independently of one another represent a hydrogen, linear or branched C ₁ -C ₄ alkyl group,
m is 0-2, and
R ₃ is selected from MR ₆ groups (where M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 0-3, and R ₆ Are H, COOH groups, or have the same meaning as R ₁ )]
b)

[Where R ₆ , m and n are as defined above]
c)

[here,
R ₆ , m and n are as defined above and R ₈ has the meaning R ₁ or the nitrogen atom to which (CH ₂ ) nR ₆ and R ₈ are bound to these Optionally substituted with a phenyl ring, or optionally 4 to 7 membered heterocyclic ring optionally fused to a benzene ring or a heterocycle as defined above. Forming
Z ⁻ is a pharmaceutically acceptable anion]
Is selected from one of the following:
A mono- or fused heterocycle is a heterocyclic ring containing 5 to 10 ring atoms in each ring and no more than 4 heteroatoms selected from S, N, O. , Pyrrole, pyrazole, furan, thiophene, indole, benzofuran, benzothiophene, imidazole, oxazole, isoxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline and any corresponding saturation And selected from partially saturated heterocycles}
A compound represented by Formula (IA)

[Wherein R ₁ , R ₂ , R ₇ and B are as defined in claim 1]
The compound of Claim 1 represented by these. Formula (IB)

[Wherein R ₇ and B are as defined in claim 1]
The compound of Claim 1 represented by these. Formula (IC):

[Wherein R ₁ , R ₂ , R ₇ and B are as defined in claim 1]
The compound of Claim 1 represented by these. Formula (IC)

[Wherein B represents the formula (IIa)

Or a group represented by formula (IIf)

Where, where
A and A ′, preferably hydrogen, where m is 0-1 and R ₃ is an MR ₆ group (where M is (CH ₂ ) n, where n is 1-3, and R6 is hydrogen, substituted or unsubstituted phenyl, phenoxy, cyclohexyl, or a single or fused heterocycle)
R ₁ is preferably selected from phenyl, cyclopentyl, cyclohexyl, benzyl, 2-thienyl and methyl optionally optionally substituted as defined above;
R ₂ is preferably selected from the group consisting of hydrogen, optionally phenyl or phenoxymethyl, cyclopentyl, cyclohexyl; 2-thienyl and methyl, optionally substituted as defined above, and
R ₇ is preferably hydrogen or a GR ₆ group (where G is (CH ₂ ) n, where n is 1 and R ₆ is hydrogen, methyl, substituted or unsubstituted phenyl Or a single or fused heterocyclic ring)]
The compound of Claim 4 represented by these. Example 27a object and the following formula

The compound of Claim 5 represented by these. Formula (IC)

[Where:
B is the formula (IIn)

Or a group represented by formula (IIq)

Or a group represented by formula (IIp)

Where, where
A and A ′ are preferably hydrogen,
m is 0-2,
n is 1-3,
R ₆ is hydrogen, phenyl, mono- or fused heterocycle, or optionally SR ₄ , SO ₂ R ₄ , CN, OR ₄ , COR ₄ , CONHR ₄ (where R ₄ is optionally substituted) phenyl optionally, benzyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl, C ₁ -C ₄ are selected from alkyl) with be optionally substituted C ₁ -C also be ₄ alkyl R ₈ is methyl, 2-thienyl-propyl, cyclohexylmethyl, optionally substituted benzyl, phenoxyethyl, 2-N, N-dimethylaminoethyl; 2-tetrahydrofurylmethyl, carboxymethyl, 2- (5-aminopyridinylmethyl), 2- (SO ₃ H) -ethyl, or (CH ₂ ) nR ₆ and R ₈ together with the nitrogen atom to which they are attached Become the following group:

Form one of the
R ₁ is preferably selected from phenyl, cyclopentyl, cyclohexyl, benzyl, 2-thienyl, optionally optionally substituted as defined above,
R ₂ is preferably selected from the group consisting of hydrogen, optionally phenyl or phenoxymethyl, cyclopentyl, cyclohexyl; 2-thienyl and methyl, optionally substituted as defined above, and
R ₇ is preferably hydrogen or a GR ₆ group, where G is (CH ₂ ) n, where n is 1 and R ₆ is hydrogen, methyl, substituted or unsubstituted phenyl Or a single or fused heterocycle), and
Z ⁻ is a pharmaceutically acceptable anion]
The compound of Claim 4 represented by these. Example 19bz object and the following formula

[Wherein Z ⁻ is a pharmaceutically acceptable anion]
The compound of Claim 7 represented by these. Formula (IE)

[Wherein R ₁ , R ₇ and B are as defined in claim 1]
The compound of Claim 1 represented by these. Z ^- is chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, 10. A compound according to claims 1-4 and 7-9 which is a pharmaceutically acceptable anion selected from mandelate, methanesulfonate and p-toluenesulfonate. A method for producing a compound represented by the general formula (I),
(a) Formula (a ')

An amino group in which the amino group is appropriately protected with a protecting group (PG) selected from t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), benzyl or methyl derivatives A mesylate derivative or alcohol group of an amino-alcohol which is reacted with an alcohol or denitrogenated at the 3 position and then appropriately protected with a protecting group (PG) at the amino group Is reacted with a similar derivative activated as a leaving group to functionalize the nitrogen atom at the 3-position to give the formula (a ”)

To yield a compound represented by
(b) The final compound or intermediate by removing the protecting group PG using the method described in the literature {and the secondary amino group using the method described in the literature) Introducing the residue R ₃ into B results in the following group:
a1)

[Wherein A and A ′ independently of one another represent a hydrogen, linear or branched C ₁ -C ₄ alkyl group,
m is 0-2, and
R ₃ is an MR ₆ group (where M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 1-3, and R ₆ is H, COOH group or the same meaning as R ₁ ]
a2)

[Wherein A and A ′, independently of one another, represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group,
m is 0-2, and
R ₃ is selected from the group MR ₆ (where M is selected from CO, CONH, SO ₂ , (CH ₂ ) n, (CH ₂ ) nCONH, where n is 0-3, and R ₆ is H, COOH group or the same meaning as R ₁ ]
Which may be further functionalized by giving rise to a compound of formula (I) selected from one of
(c) Further functionalization using the method described in the literature at the same nitrogen atom of the obtained compound, i.e. organic selected from hydrochloric acid, hydrobromic acid, oxalic acid, fumaric acid, tartaric acid Or producing an ammonium salt by treatment with an inorganic acid,
-Treatment with m-chloroperbenzoic acid or oxone and B is the group

[Where R ₆ , m and n are as defined above]
Converting to an N-oxide derivative of formula (I) selected from one of
-When treated with a suitable alkylating agent, B is

[here,
R ₆ , m and n are as defined above and R ₈ has the same meaning as R ₁ or the nitrogen to which (CH ₂ ) nR ₆ and R ₈ are attached A 4- to 7-membered heterocyclic group optionally substituted with a phenyl ring, optionally together with an atom, or optionally fused with a benzene ring or a heterocyclic ring as defined above Forming a ring, and
Z ⁻ is a pharmaceutically acceptable anion]
Converting to a quaternary ammonium salt of formula (I) selected from one of
May be allowed,
A method comprising steps.   Use of a compound according to any one of claims 1-9 for the manufacture of a medicament for the treatment of respiratory, urological or gastrointestinal diseases, urinary incontinence and bladder related diseases, irritable bowel syndrome.   The use according to claim 11, wherein the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cough, emphysema or rhinitis.   A pharmaceutical composition comprising a compound according to any one of claims 1-9 in admixture with a suitable carrier and / or excipient.